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Intracellular Signalling in Schwann cells after Nerve Injury and Repair in Healthy and Diabetic Rats
Lars B. Dahlin, MD, PhD; Lisa Martensson, PhD; Lena Stenberg, PhDStudent; Martin Kanje, PhD; Lund University
Department of Clinical Sciences Malmö - Hand Surgery, Malmö, Sweden

Introduction

A nerve injury induces profound changes in intracellular signalling in neurons and Schwann cells as a response to stress, where cells in diabetic nerves are affected directly by glucose and via glucose-induced oxidative stress. The intracellular signalling aims to put these cells into a regenerative or proliferative state with the intention to support nerve regeneration. We investigated the response after nerve injury and repair in healthy and diabetic rats.

Material & Methods

Extracellular-signal-regulated kinase 1/2 (ERK1/2) and the transcription factors c-Jun and activating transcription factor 3 (ATF-3) were studied by immunohistochemistry. These transcription factors belong to the mitogen activated protein kinase (MAPK) and the stress activated protein kinase (SAPK) pathways, respectively. Caspase 3 (Schwann cells) and neurofilaments (axons) were also stained to detect apoptosis and axonal outgrowth, respectively, in injured and repaired rat sciatic nerves in healthy and diabetic rats.

Results

After axotomy in vivo, without repair, c-Jun and pc-Jun were early up-regulated in Schwann cells. pc-Jun immunoreactivity increased in a biphasic manner. ATF-3 was also visible already at 30 min after axotomy.

In cultured sciatic nerve pieces the alterations in c-Jun, pc-Jun and ATF-3 immunoreactivity were similar to those observed in the in vivo experiments. The SAPK inhibitor, SP600125, reduced Schwann cell proliferation, but had no effect on the immunoreactivity of c-Jun, pc-Jun, ERK1/2 or ATF-3 in the Schwann cells. The MAPK inhibitor U0126 blocked the phosphorylation of ERK1/2 and reduced the proliferation of Schwann cells. The MAPK inhibitor also reduced up-regulation of c-Jun, but had no inhibitory effect on pc-Jun or ATF-3.

Axonal outgrowth was longer in healthy female rats than in diabetic female rats, but no differences was observed between healthy and diabetic male rats. Higher numbers of apoptotic and activated Schwann cells were found in the male diabetic than in the female diabetic rats. Generally, more apoptotic and activated Schwann cells were observed in diabetic rats than in healthy rats

Conclusions

Nerve injury induces activation of c-Jun and this activation, in contrast to that in neurons, is JNK independent in Schwann cells. There is an interconnection between the MAPK and SAPK pathways in Schwann cells.Diabetic rats display a higher number of activated and apoptotic Schwann cells, and axonal outgrowth is gender-related after nerve injury and repair.


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